Goals and targets for personalized therapy for HCC.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide and its incidence continues to rise. While cirrhosis underlies most cases of HCC, many molecular pathways are implicated in HCC carcinogenesis, including the TERT promoter mutation, Wnt/β-catenin, P53, Akt/mTOR, vascular endothelial growth factor receptor (VEGFR), and endothelial growth factor receptor (EGFR)/RAS/MAPK pathways. While the most widely used staging and treatment algorithm for HCC-the Barcelona Clinic Liver Cancer (BCLC) system-does not recommend systemic molecular therapy for early HCC, a variety of treatment options are available depending upon the stage of HCC at diagnosis. Determining the best treatment options must take into account not only the burden and extent of HCC, but also the patient's performance status, underlying liver function, extra-hepatic disease and co-morbidities. Radiofrequency or microwave ablation, liver resection, or liver transplantation, all potential curative therapies for HCC, should be the first-line treatments when possible. For patients who are not candidates of curative treatments, locoregional therapies such as transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and stereotactic body radiation (SBRT) can improve survival and quality of life. Sorafenib, a multi-kinase VEGF inhibitor, is the most widely used systemic chemotherapy approved as a first-line agent for unresectable or advanced HCC. Clinical trials are underway directed towards molecular therapies that target different aspects of the hepatocellular carcinogenesis cascade. Ideally, the goal of future therapy should be to target multiple pathways in the HCC cascade with combination treatments to achieve personalized care aimed at improving overall survival.